This invention relates to a method for treating diarrhoea in mammals caused by strains of bacteria producing enterotoxins, i.e. E. coli, V. cholerae and C. perfringens, by administering a 4-fluoro-.gamma.-(4-alkylpiperidino)-butyrophenone of the formula ##STR2## wherein R is lower alkyl having 1 to 6 carbon atoms, or pharmaceutically acceptable acid addition salts thereof.
The compounds have shown pronounced effect on for example travellers diarrhoea in man and diarrhoea associated with E. coli in pigs. Diarrhoea often is caused by enterotoxins from different bacterial strains that stimulate the adenylate cyclase/cyclic AMP system in the intestinal mucosa (Field, M. Ciba Foundation Symposium 42, Elsvier 1978, Amsterdam). Mucosal adenylate cyclase is also stimulated by diarrhoegenic hormones like vasoactive intestinal peptides and prostaglandins, thus supporting the concept that there exist cyclic AMP regulated transport mechanisms for electrolytes and fluid across the intestinal mucosa. By such mechanisms a prolonged stimulation of adenylate cyclase induces profuse diarrhoea followed by dehydration and sometimes death.
The mechanism of the adenylate cyclase system in the intestinate membranes is indeed complex and at present not known in detail. Although cyclic-AMP stimulated secretion appears to be electrogenic for anion it is nevertheless Na.sup.+ -dependent. Removal of Na.sup.+ (from the bothing medium) abolishes net Cl.sup.- secretion (Powel et al., Am. J. Physiol. 1974, 227, 1436).
An inhibitor of the adenylate cyclase system, chlorpromazine (The Merck Index 9th Ed., 2175) has been tested for its effect on diarrhoea caused by E. coli in piglets (Lonnroth et al., Infect. Immun. 1979, 24, 900-905). In addition to a repressing effect of chlorpromazine on diarrhoea certain disadvantages exist such as reduction in blood pressure, pronounced sedation at a dosage required for clinical effect, slow elimination and the risk of inducing contact allergy. Due to the sedation piglets treated with chlorpromazine often will be trampled and crushed by the mothersow. Lonnroth (4th International Symposium on Phenothiazines and Related Drugs, Zurich, Sept. 9-13, 1979) investigated butyrophenones as to their effect on intestinal secretion and reported that they have no or very little effect on intestinal secretion in contrast to sedative phenothiazines. However, through comprehensive research work the inventors have found that melperone (4-fluoro-.gamma.-(4-methyl-piperidino)-butyrophenone) of the formula ##STR3## (compound and process for the preparation thereof known from British Pat. No. 1,142,143), a butyrophenone characterized by few motoric, central and autonomic side effects (Ventulani et al., Pharm. Pharmacol. 1970, 22, 105), has an inhibiting effect on the intestinal adenylate cyclase system evaluated by the gut fluid secretion test (test system described by Lonnroth et al., Infect. Immun. 1979, 24, 900-905).
Hitherto a great number of different antibiotics have been used to treat diarrhoea associated with strains of E. coli. In vitro tests and clinical experience have shown a pronounced bacterial resistance against the antibiotics used. Therefore, the principle of treating these diseases through enzyme inhibition, without the risk of resistance, is superior. Furthermore, the effect of an enzyme inhibitor (such as melperone according to the invention) compared to antibiotics may be more rapid since the effect is directed to the target organ and not indirectly via the killing of the causative microorganisms. This suggestion is supported by the results in experiment II below and partly also by the trials with the previously suggested compound chlorpromazine (Lonnroth et al., Infect. Imm. 1979, 24, 900-905).
The litter morbidity of diarrhoea in piglets, 0-5 weeks old, is about 15-20% in affected herds and the mortality about 70-100% (1-2 pigs/litter) (Backstrom, Acta Vet. Scand. suppl. 41, 1973; Svendsen et al., Nord. Vet. Med. 1975, 27, 85-101).